Increasing levels of pollution in Galveston Bay, TX, are of significant concern for populations that directly depend on fishing activities. Efforts to evaluate contaminant levels in commercial fish have been largely limited to the quantification of chemical mixtures in fish tissue, but little information exists about the toxicological potential of these chemicals on consumption of contaminated seafood. The present study makes use of a human cell co-culture model, mimicking the digestive system, to address the oxidative potential of chemical mixtures in seafood. Chemical extractions were performed on fillets from three fish species and oysters collected from different areas in Galveston Bay. The resulting extracts were used to expose intestinal and liver cells before the measurement of cytotoxicity and activity of antioxidant enzymes. The pesticide 4,4'-DDE was found in nearly all samples from all sites in concentrations ranging from 0.23-9.4 µg/kg. Similarly, total PCBs found in fish and oyster tissue ranged from 0.68-65.65 µg/kg, with PCB-118 being the most common congener measured. In terms of cytotoxicity, oyster extracts led to significant cell mortality, contrary to observations for fish extracts. Antioxidant enzymes, while not directly related to the presence of chemical mixtures in tissue, presented evidence of potential increases in activity from spotted trout extracts. Observations from this study suggest the need to evaluate toxicological aspects of contaminated seafood and support the use of in vitro models for the screening of accumulated chemicals.